PROJECT SUMMARY/ABSTRACT Behavioral obesity treatment produces clinically significant weight loss; for the greatest impact, it should be made available in the primary care setting where it can reach the many patients with overweight/obesity. We have developed a 3-month automated online behavioral weight loss program, Rx Weight Loss (RxWL), and shown that it produces clinically significant weight losses among primary care patients. Our early efforts at pragmatic implementation of RxWL have been promising, and have shed light on challenges associated with implementation, and the need to study longer-term effectiveness. We therefore propose to conduct a pragmatic study to improve the implementation and effectiveness of this behavioral obesity intervention delivered in routine and representative healthcare settings. We are partnering with the Rhode Island Primary Care Physicians Corporation (RIPCPC), a large primary care network of 58 practices with 100 physicians and 16 nurse care managers. Using the framework for Effectiveness-Implementation Hybrid Designs, we will simultaneously target effectiveness and implementation to maximize the public health impact of our research. We will randomly assign half of the 16 nurse care managers, and the practices they serve, to either Basic Implementation (alerts in the electronic medical record [EMR] to direct eligible patients to RxWL), or to the Enhanced Implementation (alerts, clinician skills training to motivate and support weight loss, clinician dashboard with reports on patient progress and tools to facilitate patient engagement and behavior change). We will test the hypothesis that the Enhanced Implementation will increase the proportion of patients directed to, enrolling, and completing the weight loss program. Because maintenance of weight loss is a critical problem, this project will also involve randomization of 600 patients with overweight/obesity and type 2 diabetes, hypertension, and/or hypercholesterolemia to the 3 month RxWL intervention followed by one of three maintenance conditions: (a) Control- 9 monthly online education sessions; (b) Monthly Lessons and Feedback- 9 monthly online video lessons teaching self-regulation with automated feedback on the self-monitoring record; (c) Refresher Campaigns- 9 monthly on-line video sessions, teaching self-regulation and providing two 4-week courses with novel strategies and behavioral challenges to improve long-term outcomes. We will test the hypothesis that 12-month weight losses are better with Refresher Campaigns than Monthly Lessons and Feedback, and both are better than Control. Secondary outcomes include changes in weight, CVD risk factors, and medication use over a full 24 months. Our project is significant and innovative because: it uses an empirically validated approach to obesity treatment that is integrated into the primary care setting, leveraging existing staff and EMR capabilities; it has a dual focus on improving effectiveness and implementation; it has a pragmatic design in partnership with a large primary care network that treats a diverse patient population; and it has potential to it provides a scalable, sustainable approach that can serve as a model for broader dissemination of obesity treatment intervention.